The casein kinase-1 family of phosphotransferases are serine/threonine specific protein kinases. One member of the family, Cki-delta, has emerged as a common molecular link among neuritic plaques, neurofibrillary tangles, and granulovacuolar degeneration bodies found in Alzheimer's disease and other tauopathy brain tissues. On the basis of its substrate selectivity, colocalization with neurofibrillary and granulovacuolar degeneration lesions, and >30-fold over-expression in AD hippocampus, we have postulated that Cki-delta is involved in tau hyperphosphorylation and formation of granulovacuolar degeneration bodies. Here we propose experiments that utilize authentic human tissue samples to further test this hypothesis. Specific Aim 1 will establish the extent to which Cki-delta and other CK1 isoform mRNA, protein, and phosphotransferase activity associate with neuritic and granulovacuolar lesions during clinical progression of AD. Specific Aim 3 will focus on the mechanism of Cki-delta induction in AD, which is accompanied by large increases in its mRNA. We will determine whether mRNA induction results from increased rates of Cki-delta gene transcription, and whether it is mediated by alternative transcription start sites. The long- term goals of these studies are to clarify the relationship between granulovacuolar and neurofibrillary degeneration, to brain insight into the basis of selective neuronal susceptibility to lesion formation, and to identify signal transduction cascades that modulate Cki-delta expression in the context of human disease.